Diverse functions of DEAD-box proteins in oligodendrocyte development, differentiation, and homeostasis.

Oligodendrocytes, a type of glial cell in the central nervous system, have a critical role in the formation of myelin around axons, facilitating saltatory conduction, and maintaining the integrity of nerve axons. The dysregulation of oligodendrocyte differentiation and homeostasis have been implicated in a wide range of neurological diseases, including dysmyelinating disorders (e.g.

Inherited white matter disorders: Hypomyelination (myelin disorders).

Hypomyelinating leukodystrophies are a subset of genetic white matter diseases characterized by insufficient myelin deposition during development. MRI patterns are used to identify hypomyelinating disorders, and genetic testing is used to determine the causal genes implicated in individual disease forms. Clinical course can range from severe, with patients manifesting neurologic symptoms in infancy or early childhood, to mild, with onset in adolescence or adulthood.

Knockdown of Rab9 Recovers Defective Morphological Differentiation Induced by Chemical ER Stress Inducer or PMD-Associated PLP1 Mutant Protein in FBD-102b Cells.

Small GTP-binding proteins of the Rab family regulate intracellular vesicle trafficking across many aspects of the transport system. Among these, Rab9 is recognized for its role in controlling the transport system not only around the trans-Golgi network but also around the late endosome. However, the specific functions across different cell types and tissues remain unclear.

CRISPR/CasRx-Mediated Knockdown of Rab7B Restores Incomplete Cell Shape Induced by Pelizaeus-Merzbacher Disease-Associated PLP1 p.Ala243Val.

Pelizaeus-Merzbacher disease (PMD, currently known as hypomyelinating leukodystrophy type 1 [HLD1]) is a hereditary hypomyelinating and/or demyelinating disease associated with the proteolipid protein 1 (plp1) gene in the central nervous system (CNS). One of the major causes of this condition is incomplete or defective oligodendroglial cell myelin sheath formation triggered by endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR). The HLD1-associated Ala-243-to-Val mutation (p.

Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.

Leukodystrophies are progressive single gene disorders affecting the white matter of the brain. Several gene therapy trials are in progress to address the urgent unmet need for this patient population. We performed a comprehensive literature review of all gene therapy clinical trials listed in www.

Atlas-based assessment of hypomyelination: Quantitative MRI in Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a rare childhood hypomyelinating leukodystrophy. Quantification of the pronounced myelin deficit and delineation of subtle myelination processes are of high clinical interest. Quantitative magnetic resonance imaging (qMRI) techniques can provide in vivo insights into myelination status, its spatial distribution, and dynamics during brain maturation.

Audio-vestibular Findings in a Patient with Pelizaeus- Merzbacher Disease.

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive rare disease condition in which audiological deficit is also observed. A 4-year-old male child with PMD underwent an audiological evaluation. The results suggested normal middle ear and outer hair cells functioning, with only peak I of the auditory brainstem response present until 30 dBnHL.

Developmental Delay, Hypomyelination, and Nystagmus: Case and Approach.

Pelizaeus-Merzbacher-like disease (PMLD, OMIM #608804) is an autosomal recessive hypomyelinating leukodystrophy caused by homozygous variants in the gene. It usually presents in the first months of life with nystagmus, developmental delay, and diffuse hypomyelination on brain magnetic resonance imaging (MRI). We report a case of a 3-year-old boy that presented with nystagmus and global developmental delay.

Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy.

Objective: We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus.

Background: Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus.

Imaging Findings and MRI Patterns in a Cohort of 18q Chromosomal Abnormalities.

Background And Purpose: The abnormalities of the long arm of chromosome 18 (18q) constitute a complex spectrum. We aimed to systematically analyze their MR imaging features. We hypothesized that there would be variable but recognizable white matter and structural patterns in this cohort.

Pelizaeus-Merzbacher disease: on the cusp of myelin medicine.

Pelizaeus-Merzbacher disease (PMD) is caused by mutations in the proteolipid protein 1 (PLP1) gene encoding proteolipid protein (PLP). As a major component of myelin, mutated PLP causes progressive neurodegeneration and eventually death due to severe white matter deficits. Medical care has long been limited to symptomatic treatments, but first-in-class PMD therapies with novel mechanisms now stand poised to enter clinical trials.

A loss of function mutation in CLDN25 causing Pelizaeus-Merzbacher-like leukodystrophy.

Claudin-25 (CLDN-25), also known as Claudin containing domain 1, is an uncharacterized claudin family member. It has less conserved amino acid sequences when compared to other claudins. It also has a very broad tissue expression profile and there is currently a lack of functional information from murine knockout models.

Leukodystrophy Imaging: Insights for Diagnostic Dilemmas.

Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and thus, imaging techniques like MRI can be used for a more definitive diagnosis. These diseases are characterized as cerebral lesions with characteristic demyelinating patterns which can be used as differentiating tools.

Generation of a fluorescent oligodendrocyte reporter line in human induced pluripotent stem cells.

Human brain organoids can serve as models to study myelination, a process orchestrated by oligodendrocytes. Real-time imaging provides new insights on the communication of oligodendrocytes with neurons as well as demyelination processes in patient derived organoids. PLP1, a prominent myelin protein within the central nervous system, is associated with demyelinating diseases, such as Pelizaeus-Merzbacher.

Adaptive behavior assessed by Vineland-3 as comprehensive outcome measure in vanishing white matter.

Objectives: Investigate the results and usability of the Vineland-3 as an outcome measure in vanishing white matter patients.

Methods: A cross-sectional investigation of the Vineland-3 based on interviews with caregivers, the Health Utilities Index, and the modified Rankin Scale in 64 vanishing white matter patients.

Results: Adaptive behavior measured with the Vineland-3 is impaired in the vast majority of vanishing white matter patients and significantly impacts daily life.

An Open-Label Administration of Bioavailable-Form Curcumin in Patients With Pelizaeus-Merzbacher Disease.

Background: Two preclinical studies using mouse models of Pelizeaus-Merzbacher disease (PMD) have revealed the potential therapeutic effects of curcumin. In this study, we examined the effects of curcumin in patients with PMD.

Methods: We conducted a study administering an open-label oral bioavailable form of curcumin in nine patients genetically confirmed to have PMD (five to 20 years; mean 11 years) for 12 months (low doses for two months followed by high doses for 10 months).

Generation of Pelizaeus-Merzbacher disease (PMD) mutant (PLP1-C33Y) in induced pluripotent stem cell (iPSC) by CRISPR/Cas9 genome editing.

Genetic alterations in the PLP1 gene, i.e. point mutations and duplications, are associated with demyelinating disease Pelizaeus-Merzbacher.

Description of Phenotypic Heterogeneity in a -Related Family and Literature Review.

Introduction: Homozygous and compound heterozygous variants in , the gene encoding connexin-47 protein, cause Pelizaeus-Merzbacher-like disease type 1 or hypomyelinating leukodystrophy 2 (HLD2), a severe infantile-onset hypomyelinating leukodystrophy, and rarely some milder phenotypes like hereditary spastic paraplegia (HSP) type 44 (SPG44) and subclinical leukodystrophy. Herein, we report an Iranian -related family with intrafamilial phenotypic heterogeneity and review the literatures.

Methods: Whole-exome sequencing was performed for an Iranian proband, who was initially diagnosed as HSP case.

Preserved Auditory Steady State Response and Envelope-Following Response in Severe Brainstem Dysfunction Highlight the Need for Cross-Checking.

Objectives: Commercially available auditory steady state response (ASSR) systems are widely used to obtain hearing thresholds in the pediatric population objectively. Children are often examined during natural or induced sleep so that the recorded ASSRs are of subcortical origin, the inferior colliculus being often designated as the main ASSR contributor in these conditions. This report presents data from a battery of auditory neurophysiological objective tests obtained in 3 cases of severe brainstem dysfunction in sleeping children.

A Patient With Pelizaeus-Merzbacher Disease Caused by a c.67G>A Mutation in the PLP1 Gene.

Pelizaeus-Merzbacher disease is a tremendously rare genetic disorder caused by a mutation on the X chromosome. The mutation affects a gene critical to white matter myelination and results in significant neurological issues. Here, we present one such case of a child diagnosed with Pelizaeus-Merzbacher disease.

The natural history of Pelizaeus-Merzbacher disease caused by PLP1 duplication: A multiyear case series.

This study aimed to characterize the clinical features, developmental milestones, and the natural history of Pelizaeus-Merzbacher disease (PMD) associated with gene duplications. The study examined 16 PMD Patients ranging in age from 7 to 48 years, who had a documented gene duplication. The study examined and analyzed the medical and developmental histories of the subjects utilizing a combination of resources that included medical history questionnaires, medical record reviews, and a 31-point functional disability scale that had been previously validated.

Neuropathological characterization of the cavitating leukoencephalopathy caused by COA8 cytochrome oxidase deficiency: a case report.

COA8-related leukoencephalopathy is a recently described rare cavitating leukoencephalopathy caused by biallelic variants in the gene. Clinically, it presents heterogeneously and usually follows a bi-phasic clinical course with a period of acute onset and regression, followed by stabilization, and in some cases, even subtle improvement. We present a 4-year-old boy with a homozygous 2.

Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.

Background: The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase.